Context Neuropsychiatric symptoms of dementia are common and associated with
poor outcomes for patients and caregivers. Although nonpharmacological interventions
should be the first line of treatment, a wide variety of pharmacological agents
are used in the management of neuropsychiatric symptoms; therefore, concise,
current, evidence-based recommendations are needed.
Objective To evaluate the efficacy of pharmacological agents used in the treatment
of neuropsychiatric symptoms of dementia.
Evidence Acquisition A systematic review of English-language articles published from 1966
to July 2004 using MEDLINE, the Cochrane Database of Systematic Reviews, and
a manual search of bibliographies was conducted. Inclusion criteria were double-blind,
placebo-controlled, randomized controlled trials (RCTs) or meta-analyses of
any drug therapy for patients with dementia that included neuropsychiatric
outcomes. Trials reporting only depression outcomes were excluded. Data on
the inclusion criteria, patients, methods, results, and quality of each study
were independently abstracted. Twenty-nine articles met inclusion criteria.
Evidence Synthesis For typical antipsychotics, 2 meta-analyses and 2 RCTs were included.
Generally, no difference among specific agents was found, efficacy was small
at best, and adverse effects were common. Six RCTs with atypical antipsychotics
were included; results showed modest, statistically significant efficacy of
olanzapine and risperidone, with minimal adverse effects at lower doses. Atypical
antipsychotics are associated with an increased risk of stroke. There have
been no RCTs designed to directly compare the efficacy of typical and atypical
antipsychotics. Five trials of antidepressants were included; results showed
no efficacy for treating neuropsychiatric symptoms other than depression,
with the exception of 1 study of citalopram. For mood stabilizers, 3 RCTs
investigating valproate showed no efficacy. Two small RCTs of carbamazepine
had conflicting results. Two meta-analyses and 6 RCTs of cholinesterase inhibitors
generally showed small, although statistically significant, efficacy. Two
RCTs of memantine also had conflicting results for treatment of neuropsychiatric
symptoms.
Conclusions Pharmacological therapies are not particularly effective for management
of neuropsychiatric symptoms of dementia. Of the agents reviewed, the atypical
antipsychotics risperidone and olanzapine currently have the best evidence
for efficacy. However, the effects are modest and further complicated by an
increased risk of stroke. Additional trials of cholinesterase inhibitors enrolling
patients with high levels of neuropsychiatric symptoms may be warranted.
Up to 50% of community-dwelling elderly individuals older than 85 years
have dementia, with Alzheimer disease (AD), vascular dementia, and dementia
with Lewy bodies accounting for most cases.1,2Quiz Ref IDAlthough cognitive deficits are the clinical hallmark of dementing
illnesses, noncognitive symptoms are common and can dominate disease presentation.
These include an array of neuropsychiatric symptoms, such as agitation, aggression,
delusions, hallucinations, repetitive vocalizations, and wandering, among
other symptoms. Neuropsychiatric symptoms have been observed in
60% to 98% of patients with dementia,3- 7 especially
in later stages, and are associated with caregiver stress and depression,
as well as reduced caregiver employment and income.8- 13
Neuropsychiatric symptoms are also associated with increased hospital
lengths of stay14 and commonly lead to nursing
home placement.15- 17 Federal
expenditures for dementia are expected to triple in the next 10 years18 and 30% of the cost of caring for patients with AD
is attributed directly to the management of neuropsychiatric symptoms.19 Thus, interventions aimed at treating neuropsychiatric
symptoms could have a tremendous impact on patients, caregivers, and society.
Although there are multiple classes of drugs in use for neuropsychiatric
symptoms, including antipsychotics, anticonvulsants, antidepressants, anxiolytics,
cholinesterase inhibitors, and N-methyl-D-aspartate–receptor modulators, there is no clear standard of
care and treatment is often based on local pharmacotherapy customs. We provide
a comprehensive systematic review of pharmacological interventions for neuropsychiatric
symptoms of dementia. Our goal is to provide the generalist physician with
a clinically useful, evidence-based assessment of available pharmacological
interventions for neuropsychiatric symptoms.
To identify articles, we systematically searched the MEDLINE database
for English-language articles published between 1966 and July 2004, the Cochrane
Database of Systematic Reviews, and performed a manual search of the reference
lists of relevant retrieved articles. In MEDLINE, we combined the results
of searches in 3 separate domains: dementia (MeSH terms dementia; Alzheimer disease; dementia, vascular; or Lewy body disease), neuropsychiatric symptoms (behavior; neurobehavioral manifestations; perceptual disorders; psychomotor disorders; mood disorders; or keyword neuropsychiatric), and drug therapy (cholinesterase inhibitors; tranquilizing agents; serotonin uptake
inhibitors; anticonvulsants; valproic acid; benzodiazepines; trazodone; memantine; or psychotropic drugs). A total of 253 articles were identified through
database searches. The titles and abstracts were read by 2 authors (K.M.S.
and K.F.H.) and if the article appeared to meet inclusion criteria or if we
were uncertain, the full study was obtained. A total of 187 articles were
excluded based on reviewing titles and abstracts; therefore, 66 articles were
obtained for full review and an additional 12 articles were identified in
the manual search of references.
Studies were selected for inclusion in our systematic review if they
met all of the following inclusion criteria: double-blind, placebo-controlled,
randomized controlled trials (RCTs) or meta-analyses of RCTs; intervention
consisting of any drug therapy for patients with dementia (generally defined
in accordance with Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV)
criteria and including AD, vascular dementia, mixed, or dementia with Lewy
bodies); and outcomes for neuropsychiatric symptoms were reported (eg, hallucinations,
delusions, combativeness, verbal aggression, psychomotor agitation, wandering).
Trials reporting only depression outcomes were excluded. For the sake of summarizing
a large body of evidence succinctly, if a meta-analysis was available, results
from that analysis were presented along with any RCTs published since the
meta-analysis. Because the goal of this review was to be clinically useful,
studies were excluded if the drug was not available for use in the United
States or was no longer in wide clinical use (eg, tacrine). Studies were also
excluded if they were post hoc analyses of trials already selected for inclusion
or were duplicate publications. Data on the inclusion criteria, patients,
methods, results, and quality of each study were independently abstracted
by 2 authors (K.M.S. and K.F.H.). Disagreements were discussed and if consensus
was not reached, a third author (K.Y.) was the final arbitrator. From 78 articles
that were reviewed, only 25 RCTs and 4 meta-analyses met our inclusion criteria.
Two meta-analyses20,21 covering
12 RCTs and 2 additional RCTs22,23 of
typical (or conventional) antipsychotics were reviewed (Table 1 and Table 2). Trials
varied in length from 17 days to 16 weeks. In an early meta-analysis21 of antipsychotic drugs (including haloperidol, thioridazine,
thiothixene, chlorpromazine, trifluoperazine, and acetophenazine) covering
7 RCTs, the authors concluded that “18 of 100 patients benefited from
neuroleptics (beyond that of placebo).” There was no difference in efficacy
among the different typical antipsychotics on neuropsychiatric symptoms. An
RCT of thioridazine vs placebo23 found significant
improvements in agitation, but the trial was of poor quality with no mention
of effect size, methods for randomization and allocation concealment, or the
number of patients who completed the trial. A recent Cochrane review20 comparing haloperidol with placebo for the treatment
of agitation in dementia concluded that aggression, but not agitation, behavioral
symptoms as a whole, or clinical global impression of change was improved
by treatment with haloperidol. Whether the statistically significant result
for the aggression subscale represents a true benefit on aggression vs a chance
finding in the setting of multiple hypothesis testing is unclear. In addition,
the authors reported that dropouts due to adverse events, such as extrapyramidal
symptoms and somnolence, were more than twice as likely to occur among those
individuals randomized to haloperidol than placebo (odds ratio [OR], 2.5;
95% confidence interval [CI], 1.2-5.2). Lastly, perphenazine was not found
to be of benefit compared with placebo in a 17-day trial of hospitalized patients.22
Quiz Ref IDThere is no clear evidence that typical antipsychotic
drugs are useful for treating neuropsychiatric symptoms defined broadly. There
may be a slight benefit for haloperidol with aggression (doses of 1.2-3.5
mg/d) but it is unclear if this benefit outweighs the adverse effects, particularly
extrapyramidal symptoms and sedation. There is no evidence that any one typical
antipsychotic is more efficacious than another.
Atypical antipsychotics, also known as second-generation antipsychotics,
include clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole.
Four of 6 RCTs of atypical antipsychotics (olanzapine and risperidone) reported
benefit in the treatment of neuropsychiatric symptoms of dementia (Table 1 and Table
2).24- 29 These
trials ranged from 24 hours to 12 weeks and were all conducted among nursing
home residents, generally with moderate to severe dementia (mean Mini-Mental
State Examination score, 5.5-13.7). The first trial of oral olanzapine reported
that doses of 5 and 10 mg but not 15 mg were associated with a statistically
significant decrease in the primary outcome of the sum of 3 Neuropsychiatric
Inventory (NPI) core symptoms (agitation/aggression, hallucinations, and delusions).26 Only the 5-mg dose was associated with improvement
in total NPI score (mean, 8.8 point improvement over placebo; range, 0-144; P = .005). Another trial comparing varying doses
of olanzapine with placebo for patients with dementia-related psychosis found
no significant difference between any of the doses and placebo in either of
the primary outcomes.29 However, the authors
show that the 7.5-mg dose was better than placebo in some secondary analyses.
Finally, results from a 24-hour trial of intramuscular olanzapine (2.5 or
5.0 mg) reported a statistically significant improvement in the primary outcome
at 2 hours in those individuals treated with either dose of olanzapine compared
with placebo.27
In 1 fixed-dose trial of risperidone,25 45%
of patients receiving 1.0 mg and 50% patients receiving 2.0 mg compared with
33% receiving placebo had at least 50% reduction in the Behavioral Pathology
in Alzheimer Disease Rating Scale (BEHAVE-AD) score (P = .02
and P=.002 vs placebo, respectively). A 2.0-mg dose
was not more efficacious than 1.0-mg dose and resulted in significantly higher
adverse events, including extrapyramidal symptoms and somnolence. A subgroup
analysis of patients who were not somnolent found similar benefit for risperidone
vs placebo, suggesting that somnolence was not the mechanism for efficacy.
Another trial24 of 229 patients did not report
a significant benefit of risperidone (mean dose, 1.1 mg/d) in their primary
outcome (≥30% reduction in BEHAVE-AD total score) but did report significant
results for several secondary analyses. This trial found no difference between
risperidone and haloperidol in the primary outcome, although extrapyramidal
symptoms were more common with haloperidol. In the most recent trial of risperidone,28 mean doses of 0.95 mg/d were found to be more efficacious
than placebo on the primary outcome (4.4-point difference on Cohen-Mansfield
Agitation Inventory aggression score [scale of 84 points], P<.001) and several secondary outcomes. In this trial, 16.8% of
the patients randomized to risperidone (vs 8.8% of placebo group) had serious
adverse events, including 5 strokes and 1 transient ischemic attack. All of
the cerebrovascular events reported in the trial occurred with risperidone.
However, all of these patients also had stroke risk factors (5 of 6 patients
had atrial fibrillation).
Quiz Ref IDDoses of 5 to 10 mg/d of olanzapine or 1.0 mg/d of
risperidone appear to be at least modestly effective for treating neuropsychiatric
symptoms of dementia in patients with AD or vascular dementia. The incidence
of extrapyramidal symptoms appears to be low when receiving these doses of
olanzapine and risperidone, but somnolence remains a concern. To our knowledge,
there have been no published RCTs of clozapine, quetiapine, ziprasidone, or
aripiprazole for neuropsychiatric symptoms of dementia. Furthermore, there
have been no published RCTs designed to compare the efficacy of typical and
atypical agents.
Of the 5 RCTs that have investigated the use of serotonergic antidepressants
for the treatment of neuropsychiatric symptoms (sertraline, fluoxetine, citalopram,
and trazodone),22,30- 33 only
the trial of citalopram found benefit (Table 3 and Table 4). This 17-day
study of hospitalized patients found a 10-point change (of 168 points) in
the Neurobehavioral Rating Scale for patients randomized to citalopram compared
with a 2.3-point change for placebo (P<.001).22 Of the 7 subscales examined, only agitation and lability
were significantly improved with citalopram compared with placebo. The trial
had a high dropout rate, with more than half of patients in each group failing
to complete the study, most commonly due to lack of efficacy. Lyketsos et
al31 found sertraline to be effective in the
treatment of depression among patients with dementia. However, there was no
significant benefit of sertraline on neuropsychiatric symptoms. The authors
did report that in subgroup analyses of full responders vs nonresponders (in
terms of depression symptoms), full responders had significantly greater improvement
on nonmood items of the NPI than nonresponders.
We conclude from these trials that although serotonergic agents are
well tolerated, they do not appear to be very effective in the treatment of
neuropsychiatric symptoms of dementia other than depression.39,40
Three RCTs have investigated valproate36- 38 and
2 studies have investigated carbamazepine for neuropsychiatric symptoms34,35 (Table
3 and Table 4). Valproate
does not appear to be effective for the treatment of neuropsychiatric symptoms
of dementia whether in short- or long-acting preparations. In addition, valproate
caused significantly more adverse events than placebo, sedation being the
most common. Therefore, we do not recommend the use of valproate in the management
of neuropsychiatric symptoms of dementia. Based on 2 small trials (1 positive34 and 1 negative35),
there is currently not enough evidence of benefit to recommend the use of
carbamazepine for treatment of neuropsychiatric symptoms, especially in light
of the black box warning for hematologic toxicity and the potential drug-drug
interactions between carbamazepine and other drugs commonly prescribed to
elderly individuals. To our knowledge, there have been no published placebo-controlled
RCTs of lithium for the treatment of neuropsychiatric symptoms of dementia.
Cholinesterase Inhibitors
Two meta-analyses41,42 and
6 additional RCTs43- 48 of
various cholinesterase inhibitors with neuropsychiatric symptom outcomes have
been published (Table 5 and Table 6) with 5 of the 8 studies reporting statistically
significant benefit. In a recent meta-analysis of cholinesterase inhibitors,42 the authors reported a small but statistically significant
benefit from cholinesterase inhibitors with NPI scores (summary estimate 1.72-point
improvement vs placebo on a scale of 0-120) but not Alzheimer Disease Assessment
Scale, noncognitive portion scores. The statistically significant effect on
NPI scores was most likely driven by 2 studies of metrifonate, which was never
approved by the Food and Drug Administration for use in the United States
due to toxicities.
A Cochrane review of galantamine for AD reported 2 RCTs of galantamine
that included the NPI as an outcome.41 In one
trial, there was no benefit of either galantamine 24-mg/d or 32-mg/d dose
vs placebo.51 In the second trial, the intention-to-treat
analysis found only the 16-mg/d dose to be significantly better than placebo
(mean difference of 2.1 points, P = .03)
with no benefit for the other doses.52 One
additional RCT using 24-mg/d dose of galantamine also reported a mean treatment
difference in NPI scores of 2.2 points (P<.05).43 However, a 2-point difference on the NPI (range,
0-120) is unlikely to be clinically significant.
Four additional RCTs using donepezil have reported conflicting results.
In a 24-week trial of 208 patients in a nursing home, there was no difference
between treatment groups in the mean change in NPI scores.46 In
subgroup analyses using the NPI items as categorical outcomes, only agitation/aggression
was better for those individuals randomized to donepezil vs placebo (45% improved
vs 28%, P = .04). A 24-week trial of patients
living in the community or assisted-living facilities found a slightly larger
treatment difference of 5.6 points on the NPI in favor of donepezil (P < .001), with statistically significant
benefit on the apathy, depression, and anxiety subscales.44 A
similar magnitude of benefit was reported in a 12-week trial of 96 patients
who had significant neuropsychiatric symptoms on enrollment.48 However,
in the longest trial of cholinesterase inhibitors to date, there was no significant
difference in the mean changes in NPI scores between those individuals randomized
to donepezil (5 or 10 mg) or placebo at any time point up to 4 years of follow-up.47
An RCT of patients with mild to moderate dementia with Lewy bodies found
no difference in NPI scores between rivastigmine and placebo on either a 4-item
NPI “dementia with Lewy bodies cluster” (delusions, hallucinations,
apathy, and depression) or the full 10-item NPI.45 However,
using a predefined cutoff of at least 30% improvement, significantly more
patients receiving rivastigmine showed improvement compared with placebo (47.5%
vs 27.9%, P = .03).
Although some trials of cholinesterase inhibitors have shown statistically
significant differences, the magnitude of effect has been small and of questionable
clinical significance. Most of the patients enrolled in the cholinesterase
inhibitor trials had little neuropsychiatric symptoms with only 2 trials,46,48 requiring significant neuropsychiatric
symptoms as part of the entry criteria.
Memantine, an N-methyl-D-aspartate
receptor antagonist, was recently approved in the United States for the treatment
of moderate to severe AD. Two RCTs of community-dwelling patients with moderate
to severe AD have included neuropsychiatric symptoms as secondary outcomes
(Table 5 and Table 6).49,50 In 1
trial,49 NPI scores were not significantly
different between groups. In the other trial,50 there
was a statistically significant difference in NPI change scores, largely because
those individuals randomized to placebo got worse. Patients receiving memantine
improved their NPI score by an average of 0.1 points, whereas patients receiving
placebo declined 3.7 points (P = .002).
This difference is of unclear clinical significance. We conclude that although
memantine may be of benefit in cognitive and functional domains, there does
not appear to be a clinically significant benefit in the treatment of neuropsychiatric
symptoms for patients with moderate to severe AD.
Only 1 placebo-controlled RCT has been published on the use of benzodiazepines
for the management of neuropsychiatric symptoms of dementia.27 This
24-hour trial of intramuscular olanzapine (2.5 mg or 5 mg) vs intramuscular
lorazepam (1 mg) vs placebo is described in the section on atypical antipsychotics
in Table 2. To our knowledge, there
have been no published placebo-controlled RCTs on buspirone for the management
of neuropsychiatric symptoms of dementia.
Quiz Ref IDThere are several important methodological issues in
neuropsychiatric symptom trials that limit the interpretation of the data
and generate controversies on pharmacological management of neuropsychiatric
symptoms of dementia. One controversy is how to define clinically significant
improvement in neuropsychiatric symptoms. A particularly good example of this
problem is highlighted with the cholinesterase inhibitor trials in which several
trials reported very small but statistically significant changes in the NPI
scores. Because there are no gold standard outcomes for neuropsychiatric symptoms,
it is difficult to interpret small changes in scale scores and also to compare
results across trials using different scales to measure neuropsychiatric symptoms (Box). To address
this, we attempted to calculate standardized response means,53 but
the vast majority of trials did not present the data needed to calculate such
a measure. Clinically useful outcomes such as nursing home placement, quality
of life, and caregiver burden and depression would enhance a clinician’s
ability to interpret trial results and counsel patients and families regarding
risks and benefits of treatment.
Agitated Behavior Inventory for Dementia (ABID)
Agitation-Calmness Evaluation Scale (ACES)
Alzheimer Disease Assessment Scale, noncognitive
portion (ADAS-noncog)
Bech-Rafaelsen Mania Scale (BRMS)
Behavior Observation Scale for Intramural Psychogeriatric
Patients (GIP)
Behavior Rating Scale for Dementia (by the Consortium
to Establish a Registry for Dementia) (BRSD)
Behavioral Pathology in Alzheimer Disease Rating
Scale (BEHAVE-AD)
Brief Psychiatric Rating Scale (BPRS)
Caregiver Burden Questionnaire (CBQ)
Clinical Global Impression of Change (1 = very
much improved to 7 = very much worse) (CGIC)
Clinical Global Impression Scale (CGIS)
Clinicians Interview Based Impression of Change plus
caregiver input (CIBIC-plus)
Cohen-Mansfield Agitation Inventory (CMAI)
Hamilton Rating Scale for Depression (Ham-D)
Iowa Caregiver Stress Inventory (CSI)
Neurobehavioral Rating Scale (0 = not present
to 7 = extremely severe), derived from the Brief Psychiatric Rating
Scale (NRS)
Neuropsychiatric Inventory (usually 10 items, 120
points) (NPI)
Neuropsychiatric Inventory-Nursing Home version (12
items, 144 points) (NPI-NH)
Neuropsychiatric Inventory minus 5 “mood”
items (NPI-NM)
Overt Aggression Scale (OAS)
Positive and Negative Syndrome Scale-Excited Component
(PANSS-EC)
Revised Memory and Behavior Problem Checklist (RMBPC)
Screen for Caregiver Burden (SCB)
Social Dysfunction and Aggression Scale (SDAS-9)
Another problem with the current literature is that most trials report
on multiple outcomes from several different scales and subscales. What does
it mean if the score was significantly improved on 1 scale but not on 4 others?
This multiple comparison testing raises the concern for type I error. In addition,
when reporting their results, many of the studies downplay the negative primary
outcome while emphasizing positive secondary outcomes, especially in the abstract
and discussion sections. The majority of these trials have been funded by
the pharmaceutical industry. In this review, we have focused on the primary
outcome as specified by the authors.
The current evidence appears to suggest that, if behavioral interventions
have failed, neuropsychiatric symptoms of dementia are best treated with the
atypical antipsychotic agents (risperidone and olanzapine). However, the product
label warning for cerebrovascular events (strokes and transient ischemic attacks)
for these drugs creates a clinical dilemma. The pooled incidence of cerebrovascular
events across 6 RCTs of risperidone in the patients with dementia (N = 1721)
was reported to be 3.3% for risperidone vs 1.1% for placebo (P = .03).54 Similarly, combining
data from 5 RCTs of olanzapine in 1656 patients with dementia-related psychosis
revealed the incidence of cerebrovascular events in patients treated with
olanzapine was significantly higher than in the placebo group (1.3% vs 0.4%, P = .02), even after adjustment for age, sex,
and type of dementia.55 Therefore, physicians
considering the prescription of risperidone or olanzapine should discuss the
potential risks and benefits of such treatment with patients and their surrogate
decision makers, especially for patients with risk factors for cerebrovascular
disease.
Another area of clinical uncertainty pertains to the treatment of neuropsychiatric
symptoms in patients with dementia with Lewy bodies, increasingly recognized
as a common form of dementia.2,56,57 Very
few trials regarding the treatment of neuropsychiatric symptoms have included
patients with dementia with Lewy bodies. Therefore, no conclusions can be
drawn regarding the efficacy of drug treatment for neuropsychiatric symptoms
occurring in this setting. However, antipsychotics should be used cautiously
in patients suspected to have dementia with Lewy bodies as these patients
have been reported to have marked sensitivity, including life-threatening
neuroleptic malignant syndrome, to typical and atypical antipsychotics.57- 61 Although
dementia with Lewy bodies is characterized by fluctuating levels of impairment,
hallucinations (often visual), and parkinsonism, the diagnosis may be overlooked,
especially in later stages of the illness, until the patient experiences significant
extrapyramidal symptoms while receiving an antipsychotic. If this occurs,
the drug should be discontinued and a diagnosis of dementia with Lewy bodies
entertained.
Conclusions and perspectives
Among the many drugs in use for the treatment of neuropsychiatric symptoms,
we found only the atypical antipsychotics, risperidone and olanzapine, to
have convincing evidence of efficacy for neuropsychiatric symptoms. In addition,
trials of cholinesterase inhibitors have had remarkably consistent, albeit
small positive effects on neuropsychiatric symptoms. However, it is clear
that none of the drugs in use for neuropsychiatric symptoms offer a “magic
pill.” The effect sizes have been modest at best, with treatment differences
on the NPI scale of about 2 points for cholinesterase inhibitors and up to
8 points for olanzapine.
Potential Treatment Strategies
Quiz Ref IDThe management of neuropsychiatric symptoms in dementia
should always begin with an assessment of the patient for medical (eg, pain
and delirium) and environmental causes of the behavior. If the problem persists
after these have been addressed, nonpharmacological interventions should be
attempted before moving to drug therapy. Although a comprehensive review of
nonpharmacological interventions is outside the scope of this article, several
interventions have been shown in small studies to have varying degrees of
success including but not limited to music therapy,62,63 aromatherapy,64,65 and pet therapy.66 Caregiver
(either formal or informal) education is also an integral part of the management.67 Larger, well-designed, controlled trials of nonpharmacological
interventions are needed.
Until there are better answers, if drug therapy is to be instituted,
there are 2 reasonable approaches to the management of neuropsychiatric symptoms,
each with its merits and pitfalls. One approach would be to identify the target
symptom and choose a drug that is known to treat a symptom most closely related
to the one the patient is exhibiting. For example, one might use an antipsychotic
for psychotic symptoms or an antidepressant for anxiety symptoms, such as
repetitive vocalizations or pacing. Although this approach is intuitive, RCTs
have not been designed to confirm that this approach is effective and secondary
analyses suggest it might not be.68
An alternative approach is one guided by the current state of evidence
in combination with the goal of minimizing adverse effects (Figure). For example, although the evidence for cholinesterase inhibitors
as effective treatments for neuropsychiatric symptoms is not as convincing
as that for risperidone or olanzapine, we recommend beginning with a cholinesterase
inhibitor if the patient is not already receiving one because they are well
tolerated and may benefit cognition and function, even if they are not beneficial
for neuropsychiatric symptoms.67 Additionally,
typical antipsychotics do not appear in the suggested algorithm because there
is less evidence of benefit and more adverse effects compared with the atypical
antipsychotics.
Benzodiazepines are not part of the recommended management of neuropsychiatric
symptoms and should be avoided, especially for long-term management. Although
the only RCT using a benzodiazepine for acutely agitated patients with dementia
(Table 2)27 did
not report a significant difference in adverse events in the 24 hours after
intramuscular injection, case reports and anecdotal evidence suggest that
benzodiazepines lead to increased confusion, falls, and may paradoxically
increase agitation in patients with dementia.69,70 Consistent
with this information, the report published by the Expert Consensus Panel
for Agitation in Dementia generally recommended against the use of benzodiazepines
except for short-term or occasional use for anxiety symptoms.71 In
addition, no psychoactive medication prescribed to treat neuropsychiatric
symptoms of dementia should be continued indefinitely and attempts at drug
withdrawal should be made regularly.72 Many
patients who are prescribed antipsychotics for neuropsychiatric symptoms will
no longer need them when the drug is later discontinued.73 Physical
restraints should be avoided as they are associated with injury, not protection,
of patients who are confused.74
Directions for Future Research
Because there is no “magic pill” for neuropsychiatric symptoms
of dementia, it is especially important to continue efforts to better understand
the pathophysiology of the symptoms and whether they vary by dementia type;
perform high-quality trials of nonpharmacological treatments, especially in
combination with drug therapy; include nursing home placement and caregiver
outcomes in trials47 ; and support non–industry-funded
trials aimed specifically at treating patients with neuropsychiatric symptoms.
The results from the National Institute of Mental Health–funded Clinical
Antipsychotic Trials of Intervention Effectiveness trial75 will
be particularly valuable. This trial is a multicenter RCT comparing risperidone,
olanzapine, quetiapine, citalopram, and placebo for up to 36 weeks for the
treatment of psychosis and agitation in patients with AD.75 This
will be the first and longest placebo-controlled, head-to-head trial of atypical
antipsychotic drugs.
Corresponding Author: Kaycee M. Sink, MD,
Sticht Center on Aging, Wake Forest University School of Medicine, One Medical
Center Boulevard, Winston- Salem, NC 27157 (kmsink@wfubmc.edu).
Author Contributions: Drs Sink, Holden, and
Yaffe had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Sink, Yaffe.
Acquisition of data: Sink, Holden.
Analysis and interpretation of data: Sink,
Holden, Yaffe.
Drafting of the manuscript: Sink, Holden.
Critical revision of the manuscript for important
intellectual content: Sink, Yaffe.
Obtained funding: Sink, Yaffe.
Administrative, technical, or material support:
Yaffe.
Study supervision: Yaffe.
Financial Disclosure: Dr Yaffe has received
grant support through University of California, San Francisco from Pfizer
and Eli Lilly, and has served as a consultant for Novartis. Drs Sink and Holden
reported no financial disclosures.
Funding/Support: This work was supported in
part by a National Institute on Aging T32 training grant at the University
of California, San Francisco, and the Roena B. Kulynych Research Center, Wake
Forest University, Winston-Salem, NC (Dr Sink); and by the Paul Beeson Faculty
Scholars in Aging Research and grant NIA-R01 AG021918-01 (Dr Yaffe).
Role of the Sponsors: The sponsors had no role
in the design or conduct of the study, the data collection, interpretation
of results, or preparation and approval of the manuscript.
Acknowledgment: We thank Jay Luxenberg, MD,
for his thoughtful review of the manuscript.
1.Small GW, Rabins PV, Barry PP.
et al. Diagnosis and treatment of Alzheimer disease and related disorders:
consensus statement of the American Association for Geriatric Psychiatry,
the Alzheimer's Association, and the American Geriatrics Society.
JAMA. 1997;278:1363-1371
PubMedCrossref 2.Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A, Viramo P, Sulkava R. Dementia with Lewy bodies according to the consensus criteria in a
general population aged 75 years or older.
J Neurol Neurosurg Psychiatry. 2003;74:720-724
PubMedCrossref 3.Lyketsos CG, Steinberg M, Tschanz JT, Norton MC, Steffens DC, Breitner JC. Mental and behavioral disturbances in dementia: findings from the Cache
County Study on Memory in Aging.
Am J Psychiatry. 2000;157:708-714
PubMedCrossref 4.Finkel SI. Behavioral and psychological symptoms of dementia: a current focus
for clinicians, researchers, and caregivers.
J Clin Psychiatry. 2001;62:(suppl 21)
3-6
PubMedCrossref 5.Lyketsos CG, Lopez O, Jones B, Fitzpatrick AL, Breitner J, DeKosky S. Prevalence of neuropsychiatric symptoms in dementia and mild cognitive
impairment: results from the Cardiovascular Health Study.
JAMA. 2002;288:1475-1483
PubMedCrossref 6.Mega MS, Cummings JL, Fiorello T, Gornbein J. The spectrum of behavioral changes in Alzheimer's disease.
Neurology. 1996;46:130-135
PubMedCrossref 7.Sink KM, Covinsky KE, Newcomer R, Yaffe K. Ethnic differences in the prevalence and pattern of dementia-related
behaviors.
J Am Geriatr Soc. 2004;52:1277-1283
PubMedCrossref 8.Borson S, Raskind MA. Clinical features and pharmacologic treatment of behavioral symptoms
of Alzheimer's disease.
Neurology. 1997;48:(5 suppl 6)
S17-S24
PubMedCrossref 9.Clyburn LD, Stones MJ, Hadjistavropoulos T, Tuokko H. Predicting caregiver burden and depression in Alzheimer's disease.
J Gerontol B Psychol Sci Soc Sci. 2000;55:S2-S13
PubMedCrossref 10.Coen RF, Swanwick GR, O'Boyle CA, Coakley D. Behaviour disturbance and other predictors of carer burden in Alzheimer's
disease.
Int J Geriatr Psychiatry. 1997;12:331-336
PubMedCrossref 11.Covinsky KE, Eng C, Lui LY.
et al. Reduced employment in caregivers of frail elders: impact of ethnicity,
patient clinical characteristics, and caregiver characteristics.
J Gerontol A Biol Sci Med Sci. 2001;56:M707-M713
PubMedCrossref 12.Donaldson C, Tarrier N, Burns A. Determinants of carer stress in Alzheimer's disease.
Int J Geriatr Psychiatry. 1998;13:248-256
PubMedCrossref 13.Nagaratnam N, Lewis-Jones M, Scott D, Palazzi L. Behavioral and psychiatric manifestations in dementia patients in a
community: caregiver burden and outcome.
Alzheimer Dis Assoc Disord. 1998;12:330-334
PubMedCrossref 14.Wancata J, Windhaber J, Krautgartner M, Alexandrowicz R. The consequences of non-cognitive symptoms of dementia in medical hospital
departments.
Int J Psychiatry Med. 2003;33:257-271
PubMedCrossref 15.Steele C, Rovner B, Chase GA, Folstein M. Psychiatric symptoms and nursing home placement of patients with Alzheimer's
disease.
Am J Psychiatry. 1990;147:1049-1051
PubMed 16.Stern Y, Tang MX, Albert MS.
et al. Predicting time to nursing home care and death in individuals with
Alzheimer disease.
JAMA. 1997;277:806-812
PubMedCrossref 17.Yaffe K, Fox P, Newcomer R.
et al. Patient and caregiver characteristics and nursing home placement in
patients with dementia.
JAMA. 2002;287:2090-2097
PubMedCrossref 18.Taylor DH Jr, Sloan FA, Doraiswamy PM. Marked increase in Alzheimer's disease identified in medicare
claims records between 1991 and 1999.
J Gerontol A Biol Sci Med Sci. 2004;59:762-766
PubMedCrossref 19.Beeri MS, Werner P, Davidson M, Noy S. The cost of behavioral and psychological symptoms of dementia (BPSD)
in community dwelling Alzheimer's disease patients.
Int J Geriatr Psychiatry. 2002;17:403-408
PubMedCrossref 20.Lonergan E, Luxenberg J, Colford J. Haloperidol for agitation in dementia.
Cochrane Database Syst Rev. 2002;2:CD002852
PubMed 21.Schneider LS, Pollock VE, Lyness SA. A meta-analysis of controlled trials of neuroleptic treatment in dementia.
J Am Geriatr Soc. 1990;38:553-563
PubMed 22.Pollock BG, Mulsant BH, Rosen J.
et al. Comparison of citalopram, perphenazine, and placebo for the acute treatment
of psychosis and behavioral disturbances in hospitalized, demented patients.
Am J Psychiatry. 2002;159:460-465
PubMedCrossref 23.Stotsky B. Multicenter study comparing thioridazine with diazepam and placebo
in elderly, nonpsychotic patients with emotional and behavioral disorders.
Clin Ther. 1984;6:546-559
PubMed 24.De Deyn PP, Rabheru K, Rasmussen A.
et al. A randomized trial of risperidone, placebo, and haloperidol for behavioral
symptoms of dementia.
Neurology. 1999;53:946-955
PubMedCrossref 25.Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M. Comparison of risperidone and placebo for psychosis and behavioral
disturbances associated with dementia: a randomized, double-blind trial: Risperidone
Study Group.
J Clin Psychiatry. 1999;60:107-115
PubMedCrossref 26.Street JS, Clark WS, Gannon KS.
et al. Olanzapine treatment of psychotic and behavioral symptoms in patients
with Alzheimer disease in nursing care facilities: a double-blind, randomized,
placebo-controlled trial: the HGEU Study Group.
Arch Gen Psychiatry. 2000;57:968-976
PubMedCrossref 27.Meehan KM, Wang H, David SR.
et al. Comparison of rapidly acting intramuscular olanzapine, lorazepam, and
placebo: a double-blind, randomized study in acutely agitated patients with
dementia.
Neuropsychopharmacology. 2002;26:494-504
PubMedCrossref 28.Brodaty H, Ames D, Snowdon J.
et al. A randomized placebo-controlled trial of risperidone for the treatment
of aggression, agitation, and psychosis of dementia.
J Clin Psychiatry. 2003;64:134-143
PubMedCrossref 29.De Deyn PP, Carrasco MM, Deberdt W.
et al. Olanzapine versus placebo in the treatment of psychosis with or without
associated behavioral disturbances in patients with Alzheimer's disease.
Int J Geriatr Psychiatry. 2004;19:115-126
PubMedCrossref 30.Finkel SI, Mintzer JE, Dysken M, Krishnan KR, Burt T, McRae T. A randomized, placebo-controlled study of the efficacy and safety of
sertraline in the treatment of the behavioral manifestations of Alzheimer's
disease in outpatients treated with donepezil.
Int J Geriatr Psychiatry. 2004;19:9-18
PubMedCrossref 31.Lyketsos CG, DelCampo L, Steinberg M.
et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline
therapy, and the benefits of depression reduction: the DIADS.
Arch Gen Psychiatry. 2003;60:737-746
PubMedCrossref 32.Auchus AP, Bissey-Black C. Pilot study of haloperidol, fluoxetine, and placebo for agitation in
Alzheimer's disease.
J Neuropsychiatry Clin Neurosci. 1997;9:591-593
PubMed 33.Teri L, Logsdon RG, Peskind E.
et al. Treatment of agitation in AD: a randomized, placebo-controlled clinical
trial.
Neurology. 2000;55:1271-1278
PubMedCrossref 34.Tariot PN, Erb R, Podgorski CA.
et al. Efficacy and tolerability of carbamazepine for agitation and aggression
in dementia.
Am J Psychiatry. 1998;155:54-61
PubMed 35.Olin JT, Fox LS, Pawluczyk S, Taggart NA, Schneider LS. A pilot randomized trial of carbamazepine for behavioral symptoms in
treatment-resistant outpatients with Alzheimer disease.
Am J Geriatr Psychiatry. 2001;9:400-405
PubMed 36.Porsteinsson AP, Tariot PN, Erb R.
et al. Placebo-controlled study of divalproex sodium for agitation in dementia.
Am J Geriatr Psychiatry. 2001;9:58-66
PubMed 37.Tariot PN, Schneider LS, Mintzer J.
et al. Safety and tolerability of divalproex sodium in the treatment of signs
and symptoms of mania in elderly patients with dementia: results of a double-blind,
placebo-controlled trial.
Curr Ther Res Clin Exp. 2001;62:51-67
Crossref 38.Sival RC, Haffmans PM, Jansen PA, Duursma SA, Eikelenboom P. Sodium valproate in the treatment of aggressive behavior in patients
with dementia: a randomized placebo controlled clinical trial.
Int J Geriatr Psychiatry. 2002;17:579-585
PubMedCrossref 39.Lyketsos CG, Lee HB. Diagnosis and treatment of depression in Alzheimer's disease:
a practical update for the clinician.
Dement Geriatr Cogn Disord. 2004;17:55-64
PubMedCrossref 40.Bains J, Birks JS, Dening TR. The efficacy of antidepressants in the treatment of depression in dementia.
Cochrane Database Syst Rev. 2002;4:CD003944
PubMed 41.Olin J, Schneider L. Galantamine for Alzheimer's disease.
Cochrane Database Syst Rev. 2002;3:CD001747
PubMed 42.Trinh NH, Hoblyn J, Mohanty S, Yaffe K. Efficacy of cholinesterase inhibitors in the treatment of neuropsychiatric
symptoms and functional impairment in Alzheimer disease: a meta-analysis.
JAMA. 2003;289:210-216
PubMedCrossref 43.Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV. Efficacy of galantamine in probable vascular dementia and Alzheimer's
disease combined with cerebrovascular disease: a randomised trial.
Lancet. 2002;359:1283-1290
PubMedCrossref 44.Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E. A 24-week, randomized, double-blind study of donepezil in moderate
to severe Alzheimer's disease.
Neurology. 2001;57:613-620
PubMedCrossref 45.McKeith I, Del Ser T, Spano P.
et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomised,
double-blind, placebo-controlled international study.
Lancet. 2000;356:2031-2036
PubMedCrossref 46.Tariot PN, Cummings JL, Katz IR.
et al. A randomized, double-blind, placebo-controlled study of the efficacy
and safety of donepezil in patients with Alzheimer's disease in the nursing
home setting.
J Am Geriatr Soc. 2001;49:1590-1599
PubMedCrossref 47.Courtney C, Farrell D, Gray R.
et al. Long-term donepezil treatment in 565 patients with Alzheimer's
disease (AD2000): randomised double-blind trial.
Lancet. 2004;363:2105-2115
PubMedCrossref 48.Holmes C, Wilkinson D, Dean C.
et al. The efficacy of donepezil in the treatment of neuropsychiatric symptoms
in Alzheimer disease.
Neurology. 2004;63:214-219
PubMedCrossref 49.Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease.
N Engl J Med. 2003;348:1333-1341
PubMedCrossref 50.Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease
already receiving donepezil: a randomized controlled trial.
JAMA. 2004;291:317-324
PubMedCrossref 51.Rockwood K, Mintzer J, Truyen L, Wessel T, Wilkinson D. Effects of a flexible galantamine dose in Alzheimer's disease:
a randomised, controlled trial.
J Neurol Neurosurg Psychiatry. 2001;71:589-595
PubMedCrossref 52.Tariot PN, Solomon PR, Morris JC, Kershaw P, Lilienfeld S, Ding C. A 5-month, randomized, placebo-controlled trial of galantamine in AD:
the Galantamine USA-10 Study Group.
Neurology. 2000;54:2269-2276
PubMedCrossref 53.Rockwood K, MacKnight C. Assessing the clinical importance of statistically significant improvement
in anti-dementia drug trials.
Neuroepidemiology. 2001;20:51-56
PubMedCrossref 54.Greenspan A, Eerdekens M, Mahmoud R. Is there an increased rate of cerebrovascular events among dementia
patients? Poster presented at: 24th Congress of the Collegium Internationale
Neuro-Psychopharmacologicum (CINP); June 20-24, 2004; Paris, France
55.Cavazzoni P, Young C, Polzer J.
et al. Incidence of cerebrovascular adverse events and mortality during antipsychotic
clinical trials of elderly patients with dementia. Poster presented at: 44th Annual New Clinical Drug Evaluation Unit;
June 1-4, 2004; Phoenix, Ariz
57.Baskys A. Lewy body dementia: the litmus test for neuroleptic sensitivity and
extrapyramidal symptoms.
J Clin Psychiatry. 2004;65:(suppl 11)
16-22
PubMed 58.Ballard C, Grace J, McKeith I, Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's
disease.
Lancet. 1998;351:1032-1033
PubMedCrossref 59.McKeith IG, Ballard CG, Harrison RW. Neuroleptic sensitivity to risperidone in Lewy body dementia.
Lancet. 1995;346:699
PubMedCrossref 60.Sechi G, Agnetti V, Masuri R.
et al. Risperidone, neuroleptic malignant syndrome and probable dementia with
Lewy bodies.
Prog Neuropsychopharmacol Biol Psychiatry. 2000;24:1043-1051
PubMedCrossref 61.Walker Z, Grace J, Overshot R.
et al. Olanzapine in dementia with Lewy bodies: a clinical study.
Int J Geriatr Psychiatry. 1999;14:459-466
PubMedCrossref 62.Clark ME, Lipe AW, Bilbrey M. Use of music to decrease aggressive behaviors in people with dementia.
J Gerontol Nurs. 1998;24:10-17
PubMed 63.Gerdner LA. Effects of individualized versus classical “relaxation”
music on the frequency of agitation in elderly persons with Alzheimer's
disease and related disorders.
Int Psychogeriatr. 2000;12:49-65
PubMedCrossref 64.Ballard CG, O'Brien JT, Reichelt K, Perry EK. Aromatherapy as a safe and effective treatment for the management of
agitation in severe dementia: the results of a double-blind, placebo-controlled
trial with Melissa.
J Clin Psychiatry. 2002;63:553-558
PubMedCrossref 65.Holmes C, Hopkins V, Hensford C, MacLaughlin V, Wilkinson D, Rosenvinge H. Lavender oil as a treatment for agitated behaviour in severe dementia:
a placebo controlled study.
Int J Geriatr Psychiatry. 2002;17:305-308
PubMedCrossref 66.Cohen-Mansfield J. Nonpharmacologic interventions for inappropriate behaviors in dementia:
a review, summary, and critique.
Am J Geriatr Psychiatry. 2001;9:361-381
PubMed 67.Doody RS, Stevens JC, Beck C.
et al. Practice parameter: management of dementia (an evidence-based review):
report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2001;56:1154-1166
PubMedCrossref 68.Sultzer DL, Gray KF, Gunay I, Wheatley MV, Mahler ME. Does behavioral improvement with haloperidol or trazodone treatment
depend on psychosis or mood symptoms in patients with dementia?
J Am Geriatr Soc. 2001;49:1294-1300
PubMedCrossref 69.Wagner AK, Zhang F, Soumerai SB.
et al. Benzodiazepine use and hip fractures in the elderly: who is at greatest
risk?
Arch Intern Med. 2004;164:1567-1572
PubMedCrossref 70.Hogan DB, Maxwell CJ, Fung TS, Ebly EM. Prevalence and potential consequences of benzodiazepine use in senior
citizens: results from the Canadian Study of Health and Aging.
Can J Clin Pharmacol. 2003;10:72-77
PubMed 71. Treatment of agitation in older persons with dementia: the Expert Concensus
Panel for Agitation in Dementia.
Postgrad Med. 1998;Spec No:1-88
PubMed 72.Stoudemire A, Smith DA. OBRA regulations and the use of psychotropic drugs in long-term care
facilities: impact and implications for geropsychiatric care.
Gen Hosp Psychiatry. 1996;18:77-94
PubMedCrossref 73.Ruths S, Straand J, Nygaard HA, Bjorvatn B, Pallesen S. Effect of antipsychotic withdrawal on behavior and sleep/wake activity
in nursing home residents with dementia: a randomized, placebo-controlled,
double-blinded study: the Bergen District Nursing Home Study.
J Am Geriatr Soc. 2004;52:1737-1743
PubMedCrossref 74.Miles SH, Irvine P. Deaths caused by physical restraints.
Gerontologist. 1992;32:762-766
PubMedCrossref 75.Schneider LS, Tariot PN, Lyketsos CG.
et al. National Institute of Mental Health Clinical Antipsychotic Trials of
Intervention Effectiveness (CATIE): Alzheimer disease trial methodology.
Am J Geriatr Psychiatry. 2001;9:346-360
PubMed